CREB-binding protein
   HOME

TheInfoList



OR:

CREB-binding protein, also known as CREBBP or CBP or KAT3A, (where
CREB CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...
is cAMP response element-binding protein) is a coactivator encoded by the ''CREBBP''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
in humans, located on chromosome 16p13.3. CBP has intrinsic acetyltransferase functions; it is able to add acetyl groups to both transcription factors as well as histone lysines, the latter of which has been shown to alter chromatin structure making genes more accessible for transcription. This relatively unique acetyltransferase activity is also seen in another transcription enzyme,
EP300 Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the ''EP300'' gene. It functions as histone ace ...
(p300). Together, they are known as the
p300-CBP coactivator family The p300-CBP coactivator family in humans is composed of two closely related transcriptional co-activating proteins (or coactivators): #p300 (also called EP300 or E1A binding protein p300) # CBP (also known as CREB-binding protein or CREBBP ...
and are known to associate with more than 16,000 genes in humans; however, while these proteins share many structural features, emerging evidence suggests that these two co-activators may promote transcription of genes with different biological functions. For example, CBP alone has been implicated in a wide variety of pathophysiologies including
colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...
as well as head and neck squamous cell carcinoma. In these diseases, association of CBP with
β-catenin Catenin beta-1, also known as β-catenin (''beta''-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. β-Catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcr ...
has been shown to promote cancer cell proliferation and disease aggressiveness, whereas p300/ β-catenin leads to cell differentiation and/ or
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
. CBP has also been shown to help modulate liver function via maintenance of energy homeostasis in response to changes in cell nutrition conditions by regulating the activity of transcription factors and genes responsible for
lipogenesis In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into Adipose tissue, fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in adipose, fat. Lipogenesis encompasses both fatty aci ...
and
gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...
. CBP is also implicated in the etiologies of several other diseases including
hematologic malignancies Tumors of the hematopoietic and lymphoid tissues (American English) or tumours of the haematopoietic and lymphoid tissues (British English) are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are all ...
and other solid tumors,
diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
,
schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
,
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
, depression, and many other neurological conditions.


Structure

The functional CBP is approximately 7362 nucleotides long and encodes 2,441 amino acids. CBP does not directly interact with promoter elements; it is brought to the site via protein-protein interactions that are the result of its different structural domains complexing with other transcriptional co-activators.


Transitional adapter zinc finger domains

CBP has two transitional adapter zinc finger (TAZ) domains that each consist of four alpha helices stabilized by zinc ions. Both TAZ1 and TAZ2 domains favor the hydrophobic residues within amphipathic amino acid sequences, and their binding affinity is enhanced by the interaction of acidic residues with positive side chains. Factors that bind to TAZ2 are also potentially regulated via acetylation due to its proximity to the acetyltransferase domain (KAT).


Cysteine-histidine rich regions

Although there are three
cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
-
histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
rich domains identified within CBP, only domains 1 and 3 (CH1, CH3) have had their structural functions resolved. A number of factors that associate with CBP bind to either the CH1 or CH3 domain, or to both, despite their locations at opposing ends of the protein. To date, little is known about the interaction between these two domains. The
primary structure Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthe ...
of CH1 and CH3 has been shown to break down into consensus sequences that are capable of chelating zinc ions (Zn2+). Experiments performed also showed that the residues in these sequences are obligatory for transcriptional coactivation to occur by either CH1 or CH3. The CH2 region, located in the middle of the protein, in its acetyltransferase domain, does not contain this consensus sequence, and has not been conclusively shown to bind zinc ions.


Kinase-inducible domain interacting domain

Aka KIX domain, CREB binding domain, MYB interaction domain The kinase-inducible domain (KID) interacting domain (KIX) also is the protein domain on CBP and p300 where heterodimers form from the interaction of CBP (or p300) with other transcription factors and coactivators. It consists of three alpha and two 310 helices that have high affinity for amphipathic protein sequences. Interestingly, these helices can fold into a number of different conformers which enables the domain to maintain both a level of promiscuity while also exerting regulatory control. The KIX domain controls the rate of transcription and has been shown to be critical for hematopoietic differentiation. Some of the proteins that bind to this domain have been shown to bind competitively—such as CREB and Myb—whereas others bind via allosteric cooperation as in the case of MLL and Myb.


Bromodomain

Bromodomains (BRD) consist of approximately 110 amino acids, that function to recognize acetylated lysine molecules. They consist of four left-handed alpha helices connected by loops which form hydrophobic binding pockets. The bromodomain of CBP binds to regions of the genome are rich with acetylated lysine residues, meaning they have lost their positive charge, decreasing histone affinity for DNA, which makes the region more open and accessible for transcription. Acetylated
p53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
and
STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respon ...
have been shown to bind to CBP's bromodomain.


Lysine acetyltransferase domain

The 380 protein residue lysine acetyltransferase (KAT) domain is arguably one of the most important and identifying structural components of CBP. Its activity is regulated via
phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...
of CBP. What's interesting is that it is able to acetylate not just histones but other proteins as well. Currently there are over 100 known substrates for CBP's KAT domain including proteins such as p53, E2F-1-3, GATA-1,
MyoD MyoD, also known as myoblast determination protein 1, is a protein in animals that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of proteins kn ...
and
CREB CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...
. The ability of CBP to acetylate p53 via its KAT domain, which then increases p53's affinity for CBP's bromodomain showcases an interesting mechanism by which this unique protein can self-servingly regulate gene transcription.


Nuclear receptor coactivator binding domain

Aka interferon response factor binding domain (IBiD) The nuclear receptor coactivator binding domain (NCBD) located at the c-terminus of CBP, in its unbound state, fluctuates between multiple conformations. Binding of a target protein to NCBD will cause it to fold into three helices specifically functioned to associated with the disordered domains of its binding partners. Among the proteins known to bind to this region include ACTR (p160)--a coactivator for the thyroid and retinoid receptors, its homolog SRC-1, p53, and SMAD.


Interactions

Proteins shown to interact specifically with CBP


Function

This gene is ubiquitously expressed and is involved in the transcriptional coactivation of many different
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s. CBP has two critical mechanisms by which it is able to regulate gene expression: as an acetyltransferase, and as a protein scaffold that helps recruit and construct the complexes that are necessary for transcription or chromatin remodeling. Phosphorylation of CBP increases its acetyltransferase activity, a process hypothesized to be regulated in a cell cycle dependent manner. Recent results suggest that novel CBP-mediated post-translational N-
glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
activity alters the conformation of CBP-interacting proteins, leading to regulation of gene expression, cell growth and differentiation,


Distinction from p300

Often in scientific papers (especially in less recent ones), CBP and p300 are used interchangeably as CBP/p300. This is a reasonable amalgamation given the sequence homology, structural similarity and binding behaviors of these two proteins. However, ongoing research shows that CBP and p300 maintain distinct biological functions and should therefore not be conflated. It has been reported that despite having common histone substrates, when there are lower amounts of histone or acetyl-CoA available, CBP and p300 have different, preferred acetyltransferase substrates. In an experiment performed involving the Kaposi sarcoma-associated herpesvirus, the pathological protein (vIRF), was shown to be upregulated by CBP and repressed by p300. p300 homozygous knockout studies in mice were embryonic lethal, with improper neurulation and poor heart development occurring during their limited survival. Additionally, the fibroblasts isolated from these mice were unable to properly proliferate and were lacking the
retinoic acid receptor The retinoic acid receptor (RAR) is a type of nuclear receptor which can also act as a ligand-activated transcription factor that is activated by both all-trans retinoic acid and 9-cis retinoic acid, retinoid active derivatives of Vitamin A. ...
. Transgenically altered mice homozygous for mutated copies of CBP (missing the KAT domain), were also embryonic lethal, however instead, these mice had poor vascular angiogenesis and abnormal hematopoiesis characterized by the absence of progenitor cell proliferation and an altered hematopoietic microenvironment. The fact that both CBP and p300 homozygous knockouts were embryonic lethal suggest that these factors play a critical role in embryogenesis. The differential phenotypes of these embryos also indicate that CBP and p300 regulate different aspects of embryological development.


Role in cell cycle regulation

Studies performed in the late 1990s demonstrated that peak CBP acetyltransferase activity occurs at the transition between the G1/S phase of the
cell cycle checkpoint Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, wi ...
. Given the concentrations of CDK2 present in the cell at this stage of the cell cycle, it was hypothesized that CDK2 may be a key regulator of these post-translational modifications. It turned out that administration of cyclin E/CDK2 inhibitors did in fact inhibit the enzymatic activity of CBP's KAT domain. Other proteins that have been shown to phosphorylate CBP include
MAP Kinase A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammato ...
,
PKA In chemistry, an acid dissociation constant (also known as acidity constant, or acid-ionization constant; denoted ) is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction :H ...
and CAMK4. Ser-133 has been shown to be an important residue that is phosphorylated by PKA to initiate CBP transcriptional activity. The E2F family of transcription factors are critical for taking a cell from G1 to S phase of the cell cycle. They bind to a sequence consensus in the promoter region of genes involved in DNA replication. CBP (and p300) have been shown to interact with E2F proteins as both a coactivator, and as an acetyltransferase, the latter of which causes increased E2F DNA binding affinity. A
knockout study Gene knockouts (also known as gene deletion or gene inactivation) are a widely used genetic engineering technique that involves the targeted removal or inactivation of a specific gene within an organism's genome. This can be done through a variet ...
that was published in 2000, which used a microinjection of an antibody against CBP/p300 significantly diminished the number of cells able to progress into S phase, further supporting the idea that CBP is essential in the transcription of factors necessary G1/S phase transition. CBP is also believed to facilitate the process of DNA replication during S phase by acetylating histones around origins of replication. Acetylation of
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...
s, specifically lysine residues in the histones, weakens the electric charge interaction between the histone and DNA, causing this area to become more open and accessible for the machinery required for DNA replication. Two histone acetylation markers that have been associated with active regions include histone 3 lysine 18 acetylation (H3K18ac) and histone 3 lysine 27 acetylation (H3K27ac). It has also been shown that CBP acetylates two
endonuclease In molecular biology, endonucleases are enzymes that cleave the phosphodiester bond within a polynucleotide chain (namely DNA or RNA). Some, such as deoxyribonuclease I, cut DNA relatively nonspecifically (with regard to sequence), while man ...
s ( FEN1, DNA2) that are involved in processing
Okazaki fragments Okazaki fragments are short sequences of DNA nucleotides (approximately 150 to 200 base pairs long in eukaryotes) which are synthesized discontinuously and later linked together by the enzyme DNA ligase to create the lagging strand during DN ...
. Another key component of the cell cycle that is regulated by CBP is the anaphase promoting complex/cyclosome (APC/C). This complex consists of numerous subunits that are grouped into two subdomains, the "Arc Lamp" and the "Platform," and functions as an
E3 ubiquitin ligase A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...
that targets components related to the cell cycle such as
cyclin B Cyclin B is a member of the cyclin family. Cyclin B is a mitotic cyclin. The amount of cyclin B (which binds to Cdk1) and the activity of the cyclin B-Cdk complex rise through the cell cycle until mitosis, where they fall abruptly due to degr ...
,
securin Securin is a protein involved in control of the metaphase-anaphase transition and anaphase onset. Following bi-orientation of chromosome pairs and inactivation of the spindle checkpoint system, the underlying regulatory system, which includes securi ...
, and
PLK1 Serine/threonine-protein kinase PLK1, also known as polo-like kinase 1 (PLK-1) or serine/threonine-protein kinase 13 (STPK13), is an enzyme that in humans is encoded by the ''PLK1'' ( polo-like kinase 1) gene. Structure PLK1 consists of 603 a ...
for
proteasome Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...
degradation. Two subunits of the APC/C have been shown to directly interact with CBP: AP5, which is located in the Platform subdomain, and AP7, located in the Arc Lamp subdomain. Experiments performed using
RNAi RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known b ...
to completely suppress CBP and p300 showed significant increases in protein concentrations for those normally targeted by the APC/C, and caused a number of cells to become arrested in the mitotic phase of the cell cycle. CBP and p300 have been shown to acetylate key factors involved in different
DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...
processes, including
base excision repair Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...
,
nucleotide excision repair Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. Intercalation (biochemistry), intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single ...
and
non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair ...
. CBP and p300 play a role in the acetylation of
DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is constantly modified ...
response proteins and this
post-translational modification In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translation (biolog ...
influences their function.


Role in disease


Rubinstein–Taybi syndrome

Rubinstein–Taybi syndrome (RTS) is a rare genetic disorder that is the result of genetic mutations in either CBP or p300. RTS Type 1, which is caused by CBP mutations, for which over 500 different variations have been documented, accounts for approximately 55% of all cases, whereas RTS Type 2, which is caused by any of the nearly 120 different types of p300 mutations, accounts for only 8% of diagnosed cases. The majority of these mutations have been shown to cause loss of function of the gene via deletions, point or truncating mutations. Statistics indicate that RTS patients have and increased risk of cancer, with approximately 5% of that attributable to pediatric malignancies originating from the neural crest. Individuals with RTS frequently have skeletal abnormalities, neuroanatomical defects, and mental impairments including lower levels of intelligence, attention deficits and impaired motor coordination.


Cancer

CBP has been shown to play a role in every stage of tumor development. Due to its critical role in regulation of cell proliferation, growth, migration and apoptosis, it is considered to be an
oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
, or tumor suppressor. Contrarily To date, increased CBP activity has been implicated in a variety of different malignancies including
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
,
lung cancer Lung cancer, also known as lung carcinoma, is a malignant tumor that begins in the lung. Lung cancer is caused by genetic damage to the DNA of cells in the airways, often caused by cigarette smoking or inhaling damaging chemicals. Damaged ...
,
prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
, colorectal cancer, acute leukemias,
head and neck cancer Head and neck cancer is a general term encompassing multiple cancers that can develop in the head and neck region. These include cancers of the mouth, tongue, gums and lips (oral cancer), voice box ( laryngeal), throat ( nasopharyngeal, orophary ...
, and many others. According to the Catalog of Somatic Mutations in Cancer
COSMIC
, the most common genetic mutations in CBP are missense mutations (accounting for ~71% of all CBP mutations). The most frequent mutations occur in the KAT domain, resulting largely in either decreased or inhibited acetyltransferase activity.


Hematological malignancies

Embryonic mice heterozygous for CBP (Cbp+/-) exhibited "
extramedullary hematopoiesis Extramedullary hematopoiesis (EMH or sometimes EH) refers to hematopoiesis occurring outside of the medulla of the bone (bone marrow). It can be physiologic or pathologic. Physiologic EMH occurs during embryonic and fetal development; during this ...
, decreased bone marrow cellularity lower ratio of bone marrow to fat and hematopoietic differentiation abnormalities." By age 1, these mice had an increased incidence of leukemia or hematologic neoplasia. Interestingly, tumor sequencing showed
loss of heterozygosity In genetics, loss of heterozygosity (LOH) is a type of genetic abnormality in diploid organisms in which one copy of an entire gene and its surrounding chromosomal region are lost. Since diploid cells have two copies of their genes, one from each ...
for the
wild type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, " ...
allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...
. One explanation proposed for these experimental results is that CBP plays a role in hematopoietic stem cell self-renewal. In cases of patients diagnosed with
Acute Myeloid Leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...
(AML) and
Myelodysplastic Syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may includ ...
, CBP has been shown to gain function. This occurs via
chromosomal translocation In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes "balanced" and "unbalanced" translocation, with three main types: "reciprocal", "nonreciprocal" and "Robertsonian" transloc ...
s between CBP and other acetyltransferase called the monocytes leukemia zinc finger (MOZ), and or between MORF (MOZ-related factor) and MLL (mixed-lineage leukemia) genes. Both instances result in fused proteins in which C-terminus of CBP is lost, and the acetyltransferase domains from ''both'' proteins remain, resulting in up-regulated KAT activity and onset of disease. For patients with a relapsing case of
Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia (ALL) is a cancer of the Lymphocyte, lymphoid line of blood cells characterized by the development of large numbers of lymphoblast, immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, ...
(ALL), it was reported approximately 18% of them had CBP KAT domain mutations.


Solid tumors

CBP mutations, though relatively infrequent, have been identified in
lung cancer Lung cancer, also known as lung carcinoma, is a malignant tumor that begins in the lung. Lung cancer is caused by genetic damage to the DNA of cells in the airways, often caused by cigarette smoking or inhaling damaging chemicals. Damaged ...
. Further analysis has also revealed that during the early stages of respiratory epithelium tumorigenesis, there is increased expression in CBP as well as AP-1 and cyclin D1, factors known to be associated with CBP transcriptional activity. This over-expression may lead to downstream signaling events that favor lung tumor development.
Colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...
and
head and neck cancer Head and neck cancer is a general term encompassing multiple cancers that can develop in the head and neck region. These include cancers of the mouth, tongue, gums and lips (oral cancer), voice box ( laryngeal), throat ( nasopharyngeal, orophary ...
(HNSCC) disease severity have been linked to the association of CBP with β-catenin, a critical factor involved in the canonical Wnt signaling pathway. Association of CBP with β-catenin leads to the transcription of genes responsible for more aggressive cancer traits including the presence of cancer stem cell populations, decreased immune cell infiltration and likelihood of metastasis. Experiments studying the use of a small molecule inhibitor of β-catenin/CBP association (ICG-001), that does not block p300/β-catenin association, saw decreased carcinogenesis and increased cellular differentiation and apoptosis. Increased nuclear hormone signaling, mediated by the
androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
(AR) and
estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
(ER) receptors, are responsible for a number of
prostate The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
and
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
cases, respectively. CBP is known to interact with the AR and ER in both coactivator and acetyltransferase contexts. Inhibition of CBP KAT activity has been shown to decrease AR and ER signaling by down regulating receptor expression; this in turn suppresses tumorigenesis of both malignancies.


Metabolic homeostasis

Energy homeostasis In biology, energy homeostasis, or the homeostatic control of energy balance, is a biological process that involves the coordinated homeostatic regulation of food intake (energy inflow) and energy expenditure (energy outflow). The human brain, p ...
, which relies on a balance of
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
and
lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
s, is essential for organism survival. Diseases involving impaired
metabolic activity Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
include
obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
,
Type 2 Diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
(T2D) and nonalcoholic fatty liver disease (NAFLD). In the context equilibrium, over nutrition promotes
lipogenesis In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into Adipose tissue, fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in adipose, fat. Lipogenesis encompasses both fatty aci ...
(lipid synthesis) in response to increased glucose and insulin concentrations, and fasting promotes
β-oxidation In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl-CoA enters ...
(lipid breakdown) and
gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...
(synthesis of glucose). Experiments performed in diet-induced obese mice saw increased lipogenesis driven by over expression of sterol regulatory element binding protein 1C ( SREBP1C), which works in coordination with the carbohydrate responsive-element binding protein (
ChREBP Carbohydrate-responsive element-binding protein (ChREBP) also known as MLX-interacting protein-like (MLXIPL) is a protein that in humans is encoded by the ''MLXIPL'' gene. The protein name derives from the protein's interaction with carbohydrate r ...
). Both are transcription factors critical for lipogenesis, and both are acetylated by CBP, a post translational modification that increases their transcriptional activity. To balance the increase in lipid synthesis, the body needs to be able to export the macromolecule out of cells and storage. Microsomal triglyceride transfer protein ( MTP) is responsible for lipoprotein assembly and secretion, and it associates with an RNA helicase, DDX3, which interacts with CBP causing
HNF4 HNF4 (Hepatocyte Nuclear Factor 4) is a nuclear receptor protein mostly expressed in the liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology ...
acetylation, which in turn increases the rate of transcription of MTP in a positive feedback loop. CBP also has a role in regulation of glucose homeostasis during fasting conditions. Research has also shown that
glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medic ...
, a hormone released when the body has low blood sugar, activates cAMP response element binding protein (
CREB CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...
), which then binds to CBP as a coactivator for transcription of FOXO1.
FOXO1 Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the ''FOXO1'' gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glyco ...
is a transcription factor for enzymes including glucose-6-phosphatase and phosphoenolpyruvate carboxykinase ( PECK1), which are necessary for gluconeogenesis.


Neurological disorders

CREB has been shown to have neuroprotective properties. Because of its association with CBP, understanding the role of CBP in neurological pathways and how aberrations influence disease is becoming of increasing interest. Numerous animal models have been designed in order to evaluate changes in motor, learning and memory function in mice with CBP mutations. Conditional knockout (cKO) mice that were hemizygous for CBP or had CBP point mutations exhibited memory defects—specifically related to
long-term memory Long-term memory (LTM) is the stage of the Atkinson–Shiffrin memory model in which informative knowledge is held indefinitely. It is defined in contrast to sensory memory, the initial stage, and short-term or working memory, the second stage ...
. For mice with homozygous point mutations in their CBP KIX domain, they demonstrated impaired motor skill learning and execution. In conjunction with the neurological challenges experienced by RTS patients (lower levels of intelligence, attention deficits), CBP is attributable to a variety of neurological symptoms characteristic of many different types of diseases.


Fetal alcohol spectrum disorders

Fetal alcohol spectrum disorder Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in a person who is exposed to alcohol during gestation. FASD affects 1 in 20 Americans, but is highly misdiagnosed and underdiagnosed. The several forms of the ...
s (FASD) is a classification of diseases that all result from alcohol exposure during pregnancy. Symptoms of these disorders include poor cerebellar-dependent learning, motor coordination and impaired balance. In rats with FASD, it was shown that they had decreased concentrations of CBP and lower amounts of H3 and H4 acetylation.


Huntington's disease

Huntington's disease (HD) is a fatal, progressing neurodegenerative disorder that is the result of a genetic mutation in the
Huntingtin Huntingtin (Htt) is the protein coded for in humans by the ''HTT'' gene, also known as the ''IT15'' ("interesting transcript 15") gene. Mutation, Mutated ''HTT'' is the cause of Huntington's disease (HD), and has been investigated for this role an ...
gene causing synthesis of a mutated huntingtin (Htt) protein. Symptoms most frequently associated with this disease are movement disorders, including impaired motor function, behavioral modification and cognitive impairment that ultimately results in dementia. It has been observed in animal models that HD subjects had diminished CBP activity and decreased neuronal histone acetylation. Research has shown that mutHtt directly interacts with CBP It has been hypothesized that mutant Htt is either capable of degrading CBP, or it directly inhibits CBP's acetyltransferase domain.


Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease whose pathology is diagnosed based on the presence of neuritic amyloid beta (Aβ) plaques and neurofibrillary tau (τ) tangles. Because the exact causes of the disease are not clearly understood, there are a number of different mechanisms by which CBP is hypothesized to play a role in the progression of AD. In many cases of early-onset familial AD (FAD), there are mutations of the proteins that make up the enzyme responsible for the creation of Aβ plaques. CBP activity is decreased in the absence of these proteins ( presenilin 1 or
presenilin 2 Presenilin-2 is a protein that (in humans) is encoded by the ''PSEN2'' gene. Function Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor p ...
). Additionally, in mouse models of AD, it has been shown that there is a decrease in neuronal histone acetylation, a critical function of CBP.


Inhibition of CBP

Given the control CBP has over a wide variety of physiological processes, the development of inhibitors for CBP activity have become increasingly important as potential therapies. To date, only a fraction of what has been discovered have progressed into clinical trials.


References


Further reading

* * * * * * * * * * * * * *


External links


GeneReviews/NCBI/NIH/UW entry on Rubinstein-Taybi Syndrome
* *

* {{DEFAULTSORT:Creb-Binding Protein Transcription coregulators